This laboratory is interested in the pathogenesis of diabetes mellitus. Previous studies have focused on insulin antagonists. The present program is designed to provide insight into the observations that prediabetic subjects have a delayed insulin response to glucose and that this delay can be reversed by aminophylline, an agent capable of increasing cyclic AMP levels. Studies are proposed in isolated perfused pancreas, pancreas pieces, isolated islets of Langerhans and human subjects. Attempts will be made to correlate cyclic AMP levels, cyclase enzyme activities with the patterns of insulin release. Finally, studies of the effect of insulin antagonists upon insulin secretion patterns will be made. It is postulated that both Alpha and Beta cell lesions may exist in diabetes.